The present invention is concerned with new chemical compounds, their preparation, pharmaceutical formulations containing them and their use in medicine, particularly the prophylaxis and treatment of migraine.
Receptors which mediate the actions of 5-hydroxytryptamine (5- have been identified in mammals in both the periphery and the brain. Currently, as many as seven 5-HT receptor classes are proposed (Humphrey et al., Trends Pharmac Sci., 14, 233-236, 1993), although only the classes nominated 5-HT1, 5-HT2, 5-HT3, and 5-HT4 have established physiological roles. European Patent Specification 0313397 describes a class of 5-HT agonists which act selectively at a particular subtype of 5-HT1 receptor and are effective therapeutic agents for the treatment of clinical conditions in which a selective agonist for this type of receptor is indicated. For example, the receptor in question mediates selective cranial arterial vasoconstriction and inhibition of plasma protein extravasation into the dura mater evoked by activation of the Vth (trigeminal) nerve. The compounds described in the European specification are therefore beneficial in the treatment or prophylaxis of conditions wherein these actions are indicated, for example, migraine, a condition associated with and/or neurogenically-evoked inflammation dilation of the cranial vasculature. However, it is within the scope of the earlier application that the target tissue may be arty tissue wherein action is mediated by 5-HT1 receptors of the type referred to above.
EP-A-0486666 discloses a class of compounds having exceptional activity at the 5-HT1 receptor mentioned above and excellent absorption following oral dosing. These properties render the compounds particularly useful for certain medical applications, notably the prophylaxis and treatment of migraine, cluster headache and headache associated with vascular disorders, hereinafter referred to collectively as xe2x80x9cmigrainexe2x80x9d.
There has now been discovered a class of compounds which, although having relatively little activity themselves at the 5-HT1 receptor, act as prodrugs releasing active compound after administration. Such compounds thereby provide active compound with improved metabolic stability and bioavailability.
Thus, according to a fist aspect of the present invention there is provided a compound of formula (I): 
wherein
A is C1-6 alkyl, xe2x80x94Oxe2x80x94C1-6 alkyl, or xe2x80x94O-phenyl, or phenyl, optionally substituted by C1-3 alkyl or halogen;
n is an integer of from 0 to 3;
W is a group of formula (i), (ii) or (iii) 
wherein R is hydrogen or C1-4 alkyl, X is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94, or xe2x80x94CH2xe2x80x94, Y is oxygen or sulphur and the chiral centre * in formula (i) or (ii) is in its (S) or (R) form or is a mixture thereof in any proportions; and
Z is a group of formula (iv), (v) or (vi) 
wherein R1 and R2 are independently selected from hydrogen and C1-4 alkyl and R3 is hydrogen or C1-4 alkyl;
and salts, solvates and physiologically functional derivatives thereof.
Preferably W is a group of formula (i) and Z is a group of formula (iv)
In another aspect the present invention provides a compound of the formula (Ia) 
wherein
A is C1-6 alkyl, xe2x80x94Oxe2x80x94C1-6 alkyl, xe2x80x94O-phenyl or phenyl, optionally substituted by C1-3 alkyl or halogen;
n is an integer from 0 to 3;
R is hydrogen or C1-4 alkyl;
X is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94or xe2x80x94CH2xe2x80x94;
Y is oxygen or sulphur, and
R1 and R2 are independently selected from hydrogen and C1-4 alkyl and salts, solvates and physiologically functional derivatives thereof.
Preferred compounds of formula (Ia) are those wherein n is 1, X is xe2x80x94Oxe2x80x94 and Y is oxygen. Compounds wherein R1 and R2 are independently selected from hydrogen and methyl are preferred, with compounds wherein R1 and R2 are both methyl being particularly preferred.
Compounds of formula (I) and (Ia) are capable of existing as optical isomers. All such isomers, individually and as mixtures, are included within the scope of the present invention.
Examples of preferred compounds of the invention include:
(1) 4-[1-Benzoyl-3-[2-(dimethylamino)ethyl]indol-5-ylmethyl]oxazolidin-2-one acetate;
(2) 4-[1-Pivaloyl-3-[2-(dimethylamino)ethyl]indol-5-ylmethyl]oxazolidin-2-one acetate;
(3) 4-[1-(2xe2x80x2-toluoyl)-3-[2-(dimethylamino)ethyl]indol-5-ylmethyl]oxazolidin-2-one acetate;
(4) 4-[1-Benzyloxycarbonyl-3-[2-(dimethylamino)ethyl]indol-5-ylmethyl]oxazolidin -2-one;
(5) 4-[1-t-Butyloxycarbonyl-3-[2-(dimethylamino)ethyl]indol-5-ylmethyl]oxazolidin-2-one acetate; and
(6) 4-[1-Acetyl-3-[2-(dimethylamino)ethyl]indol-5-ylmethyl]oxazolidin-2-one acetate.
Physiologically acceptable salts are particularly suitable for medical applications because of their greater aqueous solubility relative to the parent, ie basic, compounds. Such salts must clearly have a physiologically acceptable anion. Suitable physiologically acceptable salts of the compounds of the present invention include those derived from acetic, hydrochloric, hydrobromic, phosphoric, malic, maleic, fumaric, citric, sulphuric, lactic, or tartaric acid The succinate and chloride salts are particularly preferred for medical purposes. Salts having a non-physiologically acceptable anion arc within the scope of the invention as useful intermediates for the preparation of physiologically acceptable salts and/or for use in non-therapeutic, for example, in vitro, situations.
According to a third aspect of the present invention, there is provided a compound of formula (I) or (Ia) or a physiologically acceptable salt, solvate, or physiologically functional derivative thereof for use as a therapeutic agent, specifically as a xe2x80x9c5-HT1-likexe2x80x9d receptor agonist, for example, as a carotid vasoconstrictor or as an inhibitor of neurogenic inflammation in the prophylaxis and treatment of migraine. As indicated, however, target organs for the present compounds other than the carotid vasculature are within the scope of the present invention.
The amount of a compound of formula (I) or (Ia), a salt or solvate thereof, which is required to achieve the desired biological effect will depend on a number of factors such as the specific compound, the use for which it is intended, the means of administration and the recipient. A typical daily dose for the treatment of migraine may be expected to lie in the range 0.01 to 5 mg per kilogram body weight. Unit doses may contain from 1 to 100 mg of a compound of formula (I), for example, ampoules for injection may contain from 1 to 10 mg and orally administrable unit dose formulations such as tablets or capsules may contain from 1 to 100 mg. Such unit doses may be administered one or more times a day separately or in multiples thereof. An intravenous dose may be expected to lie in the range 0.01 to 0.15 mg/kg and would typically be administered as an infusion of from (0.0003 to 0.15 mg per kilogram per minute. Infusion solutions suitable for this purpose may contain from 0.01 to 10 mg/ml.
When the active compound is a salt or solvate of a compound of formula (I) the dose is based on the cation (for salts) or the unsolvated compound.
Hereinafter references to xe2x80x9ccompound(s) of formula (I) or (Ia)xe2x80x9d will be understood to include physiologically acceptable salts and solvates thereof
According to a fourth aspect of the present invention, therefore, there are provided pharmaceutical compositions comprising, as active ingredient, at least one compound of formula (I) or (Ia) and/or a pharmacologically acceptable salt or solvate thereof together with at least one pharmaceutical carrier or excipient. These pharmaceutical compositions may be used in the prophylaxis or treatment of clinical conditions for which a xe2x80x9c5-HT1-likexe2x80x9d receptor agonist is indicated, for example, migraine. The carrier must be pharmaceutically acceptable to the recipient and must be compatible with, i.e. not have a deleterious effect upon, the other ingredients in the composition. The carrier may be a solid or liquid end is preferably formulated with at least one compound of formula (I) or (Ia) as a unit dose formulation, for example, a tablet which may contain from 0.05 to 95% by weight of the active ingredient. If desired, other physiologically active ingredients may also be incorporated in the pharmaceutical compositions of the invention.
Possible formulations include those suitable for oral, sublingual, buccal, parenteral (for example, subcutaneous, intramuscular, or intravenous), rectal, topical and intranasal administration. The most suitable means of administration for a particular patient will depend on the nature and severity of the condition being treated and on the nature of the active compound, but, where possible, oral administration is preferred.
Formulations suitable for oral administration may be provided as discrete units, such as tablets, capsules, cachets, or lozenges, each conning a predetermined amount of the active compound: as powders or granules; as solutions or suspensions in aqueous or non-aqueous liquids; or as oil-in-water or water-in-oil emulsions.
Formulations suitable for sublingual or buccal administration include lozenges comprising the active compound and, typically, a flavoured base, such as sum and acacia or tragacanth, and pastilles comprising the active compound in an inert base, such as gelatin and glycerin or sucrose and acacia.
Formulations suitable for parenteral administration typically comprise sterile aqueous solutions containing a predetermined concentration of the active compound; the solution is preferably isotonic with the blood of the intended recipient. Although such solutions are preferably administered intravenously, they may also be administered by subcutaneous or intramuscular injection.
Formulations suitable for rectal administration are preferably provided as unit-dose suppositories comprising the active ingredient and one or more solid carries forming the suppository base, for example, cocoa butter.
Formulations suitable for topical or intranasal application include ointments, creams, lotions, pastes, gel, sprays, aerosols and oils. Suitable carriers for such formulations include petroleum jelly, lanolin, polyethylene glycols, alcohols, and combinations thereof The active ingredient is typically present in such formulations at a concentration of from 0.1 to 15% w/w.
The formulations of the invention may be prepared by any suitable method, typically by uniformly and intimately admixing the active compound(s) with liquids or finely divided solid carriers, or both in the required proportions and then if necessary, shaping the resulting mixture into the desired shape.
For example, a tablet may be prepared by compressing an intimate mix comprising a powder or granules of the active ingredient and one or more optional ingredients, such as a binder, lubricant, inert diluent, or surface active dispersing agent, or by moulding an intimate mixture of powdered active ingredient and inert liquid diluent.
Aqueous solutions for parenteral administration are typically prepared by dissolving the active compound in sufficient water to give the desired concentration and then rendering the resulting solution sterile and isotonic.
Thus, according to a fifth aspect of the present invention, there is provided the use of a compound of formula (I) or (Ia) in the preparation of a medicament for the prophylaxis or treatment of a clinical condition for which a xe2x80x9c5-HT1-likexe2x80x9d receptor agonist is indicated for example; migraine.
According to a sixth aspect, there is provided a method for the prophylaxis or treatment of a clinical condition in a mammal, for example, a human, for which a xe2x80x9c5-HT1-likexe2x80x9d receptor agonist is indicated, for example, migraine, which comprises the administration to said mammal of a therapeutically effective amount of a compound of formula (I) or (Ia) or of a physiologically acceptable salt, solvate, or physiologically functional dative thereof.
The present invention also provides, in a seventh aspect, a process for the preparation of a compound of formula (I) or (Ia) This process comprises reaction of a compound of formula (II). 
wherein W, Z and n are as hereinbefore defined, with a compound of formula (III) 
wherein A is as hereinbefore defined.
The reaction is preferably carried out in the presence of a base such as an organic base, for example triethylamine, pyridine or Hunig""s base, or an inorganic base for example sodium hydride or potassium carbonate. Sodium hydride is preferred. The reaction may be cared out in polar aprotic solvents such as dimethylformamide, dimethylsulphoxide or in chlorinated solvents such as dichloromethane. Dimethylformamide is the preferred solvent The reaction may be carried out in the temperature range 0- 100xc2x0. 0xc2x0 to room temperature is preferred.
Where it is desired to prepare a compound of formula (Ia), a compound of formula (IIa) 
wherein X, Y, R, n, R1 and R2 are as hereinbefore defined may be used in place of the compound of formula (II).
Compounds of formula (II) and (IIa) can be made according to the methods described in EP A-0486666, incorporated herein by reference. Compounds of formula (III) are commercially available or can be readily prepared by those skilled in the art using known methods.
Alternatively, compounds of formula (I) or (Ia) may be prepared by reaction of a compound of formula (II) or (IIa) with a compound of formula (IV) 
wherein A is as hereinbefore defined.
The reaction is preferably carried out in the presence of a base such as an organic base, for example triethylamine, pyridine or dimethylamino pyridine or an inorganic base for example sodium hydride or potassium carbonate. Dimethylaminopyridine is preferred when it is desired to make the compound 4-[1-t-Butyloxycarbonyl-3-[2-(dimethylamino)ethyl]indol-5-ylmethyl] oxazolidin-2-one acetate. Sodium hydride is the preferred base when it is desired to make the compound 4-[1-Acetyl-3-[2-(dimethylamino)ethyl]indol-5-ylmethyl]oxazolidin-2-one acetate. The reaction may be carried out in polar aprotic solvents such as acetonitrile, dimethylformamide, dimethylsulphoxide or in chlorinated solvents such as dichloromethane. Acetonitrile is the preferred solvent for synthesis of the compound 4-[1-t-Butyloxycarbonyl-3-[2-(dimethylamino)ethyl]indol-5-yl methyl]oxazolidin-2-one acetate. Dimethylformamide is the preferred solvent for synthesis of the compound 4-[1-Acetyl-3-[2-(dimethylamino)ethyl]indol-5-ylmethyl]oxazolidin-2-one acetate. The reaction may be carried out in the temperature range 0-100xc2x0. 0xc2x0 to room temperature is preferred.
Compounds of formula (IV) are commercially available or can be readily prepared by those skilled in the art using known methods.
Salts, solvates and physiologically functional derivatives of Compounds of formula (I) or (Ia) may be prepared from compounds of formula (I) or (Ia) using standard techniques known in the art.